Biochemistry and nutrition for USMLE Step 1

A 6-month-old infant presents with hepatomegaly, hypoglycemia after short fasts, lactic acidosis, hyperuricemia and hyperlipidemia. Muscle strength is normal. Liver biopsy shows markedly increased glycogen with normal structure. Which enzyme is most likely deficient?

1. Glucose-6-phosphatase correct Correct. This is Von Gierke disease (type I). Glucose-6-phosphatase is the enzyme the liver needs to release free glucose, whether from breaking down glycogen (glycogenolysis) or from building new glucose (gluconeogenesis). Without it, the liver cannot release glucose at all, so fasting hypoglycemia starts early and is severe. The blocked pathway pushes extra substrate toward lactate, uric acid, and triglycerides.
2. Branching enzyme Wrong. Missing branching enzyme causes Andersen disease, with liver scarring (cirrhosis) and failure to thrive from abnormally branched glycogen. The biopsy here shows glycogen with a normal structure, which rules this out.
3. Muscle glycogen phosphorylase Wrong. Missing this enzyme causes McArdle disease, which affects only the muscles: exercise intolerance, cramps, muscle breakdown that shows up as myoglobin in the urine (myoglobinuria), and lactate that fails to rise with exercise. The liver and blood glucose stay normal.
4. Debranching enzyme Wrong. Missing this enzyme causes Cori disease (type III), which gives milder fasting hypoglycemia, glycogen with an abnormal structure, and normal lactate, because gluconeogenesis still works.
5. Lysosomal acid alpha-1,4-glucosidase Wrong. This enzyme is missing in Pompe disease, which enlarges the heart (cardiomegaly), causes floppy muscles (hypotonia), and leads to early death. Blood glucose stays normal in Pompe disease because the cell's normal way of using glycogen, outside the lysosome, still works.

The point: Sort the glycogen storage diseases by which organ is affected and whether lactate rises. Type I (Von Gierke): liver, severe fasting hypoglycemia, HIGH lactate. Type III (Cori): milder, normal lactate. Type V (McArdle): muscle only. Type II (Pompe): heart.

Source: USMLE Content Outline — biochemistry and nutrition NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator

A 3-year-old boy has coarse facial features, corneal clouding, hepatosplenomegaly and developmental delay. Urinary glycosaminoglycans are elevated. A second boy has the same features except that his corneas are CLEAR and he has severe behavioural disturbance. Which enzyme is deficient in the second boy?

1. Hexosaminidase A Wrong. Missing hexosaminidase A causes Tay–Sachs disease, with a cherry-red spot in the eye but NO enlarged liver or spleen, which is the key difference from Niemann–Pick disease.
2. Beta-glucocerebrosidase Wrong. Missing beta-glucocerebrosidase causes Gaucher disease, with an enlarged liver and spleen (hepatosplenomegaly), painful bone episodes (bone crises), and macrophages that look like crumpled tissue paper under the microscope, without excess glycosaminoglycans in the urine.
3. Sphingomyelinase Wrong. Missing sphingomyelinase causes Niemann–Pick disease, with a cherry-red spot in the eye, enlarged liver and spleen, and foam cells. This is not a mucopolysaccharidosis either.
4. Alpha-L-iduronidase Wrong. Missing alpha-L-iduronidase causes Hurler syndrome (MPS I), which is autosomal recessive and causes CORNEAL CLOUDING. That matches the first boy, not the second.
5. Iduronate sulfatase correct Correct. This is Hunter syndrome (MPS II). It is X-linked, spares the cornea, keeps it clear, and causes aggressive behavior. A memory trick that works well on the exam: hunters need clear sight to aim, and they are aggressive.

The point: Both mucopolysaccharidoses cause coarse facial features and problems with the airway and joints. Hurler syndrome: missing alpha-L-iduronidase, autosomal recessive, cloudy cornea. Hunter syndrome: missing iduronate sulfatase, X-linked, clear cornea, aggressive behavior.

Source: USMLE Content Outline — biochemistry and nutrition NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator

A 24-year-old man of Mediterranean descent develops jaundice, dark urine and a hemoglobin fall from 14 to 8.5 g/dL three days after starting primaquine. The blood film shows bite cells and Heinz bodies. Which biochemical consequence of the enzyme defect explains the hemolysis?

1. Defective spectrin in the membrane skeleton Wrong. A defective spectrin protein describes hereditary spherocytosis, with round-shaped red cells (spherocytes), a raised MCHC, a positive osmotic fragility test, and an enlarged spleen. It is not triggered by a drug like this case is.
2. Failure of ATP production by glycolysis Wrong. Failure of ATP production by glycolysis describes pyruvate kinase deficiency, which causes ongoing hemolysis from birth rather than sudden hemolysis triggered by an oxidant drug, and it does not cause Heinz bodies.
3. Absent GPI anchors for CD55 and CD59 Wrong. Missing GPI anchors for CD55 and CD59 describes paroxysmal nocturnal hemoglobinuria, with complement destroying red cells inside blood vessels and a tendency to form blood clots, diagnosed using flow cytometry.
4. Failure to regenerate NADPH, so glutathione cannot be kept reduced correct Correct. Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting step of the pentose phosphate pathway, and it is the red blood cell's only source of NADPH. Without NADPH, the cell cannot keep its glutathione (an antioxidant) in its active, reduced form. Oxidized hemoglobin then clumps together as Heinz bodies, and macrophages in the spleen bite these clumps out of the cell.
5. Reduced beta-globin chain synthesis Wrong. Reduced beta-globin chain production describes beta-thalassemia, with small-cell (microcytic) anemia, target cells, and a raised HbA2 level, present for life rather than triggered by a drug.

The point: G6PD deficiency is X-linked. Triggers include primaquine, dapsone, sulfonamides, nitrofurantoin, fava beans, and infection, which is actually the most common trigger of all. Test G6PD levels AFTER the episode has passed, because during active hemolysis, the surviving young red cells can give a falsely normal reading.

Source: USMLE Content Outline — biochemistry and hematology NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator